The Role of Anaplastic Lymphoma Kinase in Human Cancers

2013 ◽  
Vol 09 (02) ◽  
pp. 149 ◽  
Author(s):  
Alejandro García-Regalado ◽  
Claudia Haydée González-De la Rosa ◽  
◽  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Activity ◽  
New Drugs ◽  
Tyrosine Kinase Activity ◽  
Mutant Proteins ◽  
Anaplastic Lymphoma ◽  
Attractive Therapeutic Target ◽  
Pathway Inhibition

The anaplastic lymphoma kinase (ALK) is a receptor with tyrosine kinase activity, which regulates the development and maintenance of the nervous system. Mutations or amplification in ALK promote tumorogenesis and progression of diverse types of cancer, which makes it an attractive therapeutic target against cancer diseases. Inhibition of its tyrosine kinase activity with small molecules, such as crizotinib, reveals tumor reversion; however, secondary mutations and amplification of the gene mediate resistance to treatment. In this article, we discuss the emerging role of possible therapeutic targets that could overcome the resistance to ALK inhibition in cancer, such as inhibition of other kinases involved in the pathway, inhibition of ALK mutant proteins through the development of new drugs based on its crystallography, and the use of antibodies against ALK.

scholarly journals p130Cas mediates the transforming properties of the anaplastic lymphoma kinase

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3907-3916 ◽  
Author(s):  
Chiara Ambrogio ◽  
Claudia Voena ◽  
Andrea D. Manazza ◽  
Roberto Piva ◽  
Ludovica Riera ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Activity ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Lymphoid Cells ◽  
Src Tyrosine Kinase ◽  
Anaplastic Lymphoma ◽  
Proteomic Approach

Translocations of the anaplastic lymphoma kinase (ALK) gene have been described in anaplastic large-cell lymphomas (ALCLs) and in stromal tumors. The most frequent translocation, t(2;5), generates the fusion protein nucleophosmin (NPM)–ALK with intrinsic tyrosine kinase activity. Along with transformation, NPM-ALK induces morphologic changes in fibroblasts and lymphoid cells, suggesting a direct role of ALK in cell shaping. In this study, we used a mass-spectrometry–based proteomic approach to search for proteins involved in cytoskeleton remodeling and identified p130Cas (p130 Crk-associated substrate) as a novel interactor of NPM-ALK. In 293 cells and in fibroblasts as well as in human ALK-positive lymphoma cell lines, NPM-ALK was able to bind p130Cas and to induce its phosphorylation. Both of the effects were dependent on ALK kinase activity and on the adaptor protein growth factor receptor–bound protein 2 (Grb2), since no binding or phosphorylation was found with the kinase-dead mutant NPM-ALKK210R or in the presence of a Grb2 dominant-negative protein. Phosphorylation of p130Cas by NPM-ALK was partially independent from Src (tyrosine kinase pp60c-src) kinase activity, as it was still detectable in Syf-/- cells. Finally, p130Cas-/- (also known as Bcar1-/-) fibroblasts expressing NPM-ALK showed impaired actin filament depolymerization and were no longer transformed compared with wild-type cells, indicating an essential role of p130Cas activation in ALK-mediated transformation.

Different structural alterations upregulate in vitro tyrosine kinase activity and transforming potency of the erbB-2 gene

1988 ◽  
Vol 8 (12) ◽  
pp. 5570-5574
Author(s):  
O Segatto ◽  
C R King ◽  
J H Pierce ◽  
P P Di Fiore ◽  
S A Aaronson
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Transmembrane Domain ◽  
3T3 Cells ◽  
Tyrosine Kinase Activity ◽  
Oncogenic Potential ◽  
Mutant Proteins ◽  
Nih 3T3 ◽  
Abnormal Level

Compared with normal erbB-2 gp185, mutant erbB-2 proteins generated by mutations either in the transmembrane domain or by NH2-terminal deletion are able to transform NIH 3T3 cells at a 10- to 100-fold greater efficiency. Mutant proteins of both classes show increased tyrosine kinase activity, suggesting that an abnormal level of receptor-associated tyrosine kinase activity is a major determinant of erbB-2 oncogenic potential.

Identification of surrogate markers for determining drug activity using proteomics

2003 ◽  
Vol 31 (6) ◽  
pp. 1488-1490 ◽  
Author(s):  
C.M. McClelland ◽  
W.J. Gullick
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Drug Evaluation ◽  
New Drugs ◽  
Hydroxyl Groups ◽  
Surrogate Markers ◽  
Tyrosine Kinase Activity ◽  
Drug Activity

In a high proportion of human carcinomas overexpression of the EGFR (epidermal growth factor receptor), a receptor tyrosine kinase, represents a potential target for cancer treatment. EGFR is induced to dimerize through ligand binding which activates the tyrosine kinase activity of the receptor. This catalyses the transfer of ATP's γ-phosphate to hydroxyl groups of tyrosine residues on the receptor, creating binding sites that recruit downstream signalling proteins. New drugs, SMTKIs (small-molecule tyrosine kinase inhibitors), have been designed to inhibit the tyrosine kinase activity of the receptor, producing an anti-tumour effect. The development of surrogate markers to determine the drug activity of these new inhibitors would be of great benefit in drug evaluation and in the subsequent management of patient disease. This review describes current treatments of cancer using tyrosine kinase inhibitors and the use of proteomic analysis to identify possible markers of activity of these new drugs.

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